A facile and economic method for the synthesis of (S)-N-Boc-3′-hydroxyadamantylglycine

A facile and economic method for the synthesis of (S)-N-Boc-3′-hydroxyadamantylglycine
Li, Jie; Jiang, Xue; Gan, Run; Zhang, Ming; Pan, Xinmei; Hu, Xiangnan
2016-01-13 00:00:00
(S)-N-Boc-3′-hydroxyadamantylglycine (I) is an important intermediate of saxagliptin for type 2 diabetes mellitus (T2DM). It was prepared from 1-adamantanecarboxylic acid(1) via mild reaction with sulfuric acid/nitric acid, VHA reagent (SOCl2/DMF) and sodium diethyl malonate, then was treated with hydrolysis, decarboxylation, alkalization and oxidation to give 2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid (4), then through oximation, reduction and (Boc)2O protection to give the N-Boc-3′-hydroxyadamantylglycine(6), then was treated with quinidine to get (S)- N-Boc-3′-hydroxyadamantylglycine(I) and quinine to get (R)–N-Boc-3′-hydroxyadamantylglycine(II). Finally, Compound II was racemized by dicyclohexylcarbodiimide (DCC) and sodium hydride (NaH) to afford compound 6. In this route, the overall yield of preparing compound I was about 35 % and the enantiomeric excess (ee) reach to 99 %. This route provided a novel idea for the preparation of (S)-N-Boc-3′-hydroxyadamantylglycine.
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A facile and economic method for the synthesis of (S)-N-Boc-3′-hydroxyadamantylglycine

Abstract

(S)-N-Boc-3′-hydroxyadamantylglycine (I) is an important intermediate of saxagliptin for type 2 diabetes mellitus (T2DM). It was prepared from 1-adamantanecarboxylic acid(1) via mild reaction with sulfuric acid/nitric acid, VHA reagent (SOCl2/DMF) and sodium diethyl malonate, then was treated with hydrolysis, decarboxylation, alkalization and oxidation to give 2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid (4), then through oximation, reduction and (Boc)2O protection to give the N-Boc-3′-hydroxyadamantylglycine(6), then was treated with quinidine to get (S)- N-Boc-3′-hydroxyadamantylglycine(I) and quinine to get (R)–N-Boc-3′-hydroxyadamantylglycine(II). Finally, Compound II was racemized by dicyclohexylcarbodiimide (DCC) and sodium hydride (NaH) to afford compound 6. In this route, the overall yield of preparing compound I was about 35 % and the enantiomeric excess (ee) reach to 99 %. This route provided a novel idea for the preparation of (S)-N-Boc-3′-hydroxyadamantylglycine.